Submissions for variant NM_020366.4(RPGRIP1):c.3618-1_3621del

dbSNP: rs1594280740

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001005011	SCV001164573	pathogenic	Leber congenital amaurosis 6	2018-12-03	criteria provided, single submitter	research	The heterozygous c.3618-1_3621delGTTTA variant in RPGRIP1 was identified by our study, in the compound heterozygous state, along with another pathogenic variant, in one individual with Leber congenital amaurosis (PMID: 30072743). Trio exome analysis showed this variant to be de novo. The c.3618-1_3621delGTTTA variant in RPGRIP1 has not been previously reported in individuals with Leber congenital amaurosis and was absent from large population studies. This variant affects the invariant region (+/- 1/2) of the splice consensus sequence by activating a cryptic splice site and is predicted to cause altered splicing leading to a frameshift and an abnormal or absent protein. Loss of function of the RPGRIP1 gene is an established disease mechanism in autosomal recessive Leber Congenital Amaurosis. The presence of this variant in combination with a reported pathogenic variant and in an individual with Leber congenital amaurosis increases the likelihood that the c.3618-1_3621delGTTTA variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis in an autosomal recessive manner based on the predicted impact of the variant and de novo inheritance. ACMG/AMP Criteria applied: PM2, PVS1, PS2, PM3 (Richards 2015).
Blueprint Genetics	RCV001074771	SCV001240366	likely pathogenic	Retinal dystrophy	2019-05-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001005011	SCV002045297	pathogenic	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001800914	SCV002045308	pathogenic	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV001860573	SCV002242833	pathogenic	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2021-05-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with early onset retinal dystrophy (PMID: 26047050, 30072743). This variant is also known as c.3618–1_3621del5. ClinVar contains an entry for this variant (Variation ID: 814005). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 22 of the RPGRIP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016).
3billion	RCV001800914	SCV002521618	pathogenic	Cone-rod dystrophy 13	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000814005). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.